HIV-associated neurocognitive disorders (HAND) continue to affect people with HIV despite the advent of highly active antiretroviral therapy (HAART). While the incidence of severe HIV-associated dementia (HAD) has decreased since the introduction of HAART, the prevalence of milder and chronic forms of HIV central nervous system (CNS) disease and HIV-associated major depressive disorder remains high. Converging evidence from clinical and laboratory studies suggest the hypothesis that the toxic actions of low-level expression of multiple HIV-1 products are key to persistent central nervous system HIV disease despite viral suppression in the context of HAART. In fact, HIV-associated neurocognitive disorders in the setting of viral suppression by HAART do not correlate with indicators of florid HIV-replication such as high plasma HIV-1 viral load and low CD4+ counts. Conversely, neurocognitive disorders in the setting of HAART correlate with markers of synaptodendritic injury, such as altered patterns of presynaptic synaptophysin and postsynaptic microtubule associated protein 2 (MAP2) that can also be induced in the absence of HIV-1 infection and replication in Tg mice of HIV-1 gp120 or Tat and in neuronal cultures treated with recombinant gp120. However, while the effects of gp120 and Tat have been mostly studied in isolation, other HIV-1 proteins including gp41, Vpr, Rev, and Vpu - although not Gag and Pol - possess neurotoxic potential. This suggests that the combined action of multiple HIV-1 products may contribute to neuronal dysfunction and its evolving phenotype in the HAART setting. To address this scientific knowledge gap, here we propose to establish and characterize a transgenic mouse model to probe the effects of concomitant low level expression of multiple HIV-1 products in disease-relevant cells of the microglia/macrophage lineage. Since strains isolated from patients with HIV-1 dementia have distinct neurotoxic activities, the proposed mouse model will be based on the neurotropic JR-CSF HIV-1 clone, while most HIV-1 Tg lines are based on the T-tropic pNL4-3. The proposed HIV-1 Tg model differs from all previously established models because it will have concomitant expression of multiple proteins of a neurotropic HIV-1 clone, it will be inducible by doxycycline and, lastly, expression of the transgene will be targeted to cells of the microglia/macrophage lineage. No existing small animal model possesses all of these characteristics. The lack of viral replication in the proposed Tg mice, while motivated by the aforementioned hypothesis, will have the added practical benefit of greatly facilitating electrophysiological and behavioral studies. Ultimately, the proposed Tg mice will allow mechanistic studies aimed at the generation of new pathogenetic hypotheses of HIV-associated neurocognitive disorders in the setting of HAART and their interaction with drugs of abuse. PUBLIC HEALTH RELEVANCE: Persistent central nervous system HIV disease despite viral suppression in the context of HAART represents a mounting clinical challenge. Evidence suggests that the toxic actions of low-level HIV-1 products are key in the neuropathogenesis of persistent central nervous system HIV disease despite viral suppression in the context of HAART. The proposed study will establish and characterize a new small animal model of neuroAIDS in the HAART era to aid in the development of novel pathogenetic hypotheses and potential therapeutic approaches with the long-term goal of generating new hypotheses on the pathogenesis of HIV-1-induced neurotoxicity and the interaction of HIV-1 infection and drug abuse on cognition and motivation as well as the investigation of novel therapeutic strategies for neuroAIDS.